The hypothesis to be examined is: A major contribution to the MS lesion is made by a) activation signals and b) amplification of specific cytotoxic processes that are normally below detectable levels. These signals and amplification mechanisms are mediated by non-lethal ligands found within the CNS. The oligodendroglial cell is the cell in the CNS most affected by these processes. The presence of small numbers of specifically activated lymphocytes within the CSF, specific antibodies in CSF to brain-associated antigens (MBP, oligodendroglial cells), and putative auto-sensitizing self antigens within the CNS compartment suggest a continuous subclinical immune response is being maintained within the CNS from the time of some primary immunization to an exogenous infectious agent. A secondary event such as a) release of brain-associated mitogens, b) an unrelated antigenic signal, c) accumulation of immune complexes or C(3), or d) the activation of nonspecific lymphocytes, may in fact enhance this normally weak and undetectable, but specific lethal cytotoxicity of effector cells toward brain-associated antigens to a detectable level. The methodology to be used is designed to test cytotoxicity at the single cell level in agarose using as few as 5000 effector cells and thus is appropriate for examining cells in the cerebrospinal fluid. The first step will be to assess the presence of effector cells for nonsp]ecific amplification of cytotocicity within the CNS in direct and enhanced ADCC; Enhanced ADCC will include enhancement of IgG mediated killing by IgM, C3 immune complexes, shared antigens, and lectins. Lectin dependent killing (LDCC) and immune complex activated killing will be examined. Nonlethal ligands will thus be artificially provided in model systems with phenotypically defined targets. The second step will be to assess MS serum, CSF or in vi tro products of MS lymphocytes for such soluble effector or ligand molecules. Lastly, the defined targets will be replaced by the oligodendroglial cell target for MS effector cells and soluble CNS ligands as cross linking activator/amplifier molecules. It is the purpose of this grant to define ancillary mechanisms of inflammation with MS brains so that appropriate therapeutic modalities can be chosen.